Optimizing the dynamics of bone turnover with genetic algorithm.

Control systems and the modeling strategies are not only limited to engineering problems. These approaches can be used in the field of bio-mathematics as well and modern studies have promoted this approach to a great extent. The computational modeling and simulation of bone metastasis is painful yet critical after cancer invades the body. This vicious cycle is complex, and several research centers worldwide are devoted to understanding the dynamics and setting up a treatment strategy for this life-threatening behavior of cancer. Cancerous cells activation and the corresponding process of metastasis is reported to boost during the periodic waves of COVID-19, due to the inflammatory nature of the infection associated with SARS-2 and its variants. The bone cells are comprised of two types of cells responsible for bone formation and resorption. The computational framework of such cells, in spatial form, can help the researchers forecast the bone dynamics in a robust manner where the impact of cancer is incorporated into the computational model as a source of perturbation. A series of computational models are presented to explore the complex behavior of bone metastasis with COVID-19 induced infection. The finite difference algorithm is used to simulate the nonlinear computational model. The results obtained are in close agreement with the experimental findings. The computational results can help explore the vicious cycle's fate and help set up control strategies through drug therapies.

Forecasting the action of CAR-T cells against SARS-corona virus-II infection with branching process.

The CAR-T cells are the genetically engineered T cells, designed to work specifically for the virus antigens (or other antigens, such as tumour specific antigens). The CAR-T cells work as the living drug and thus provides an adoptive immunotherapy strategy. The novel corona virus treatment and control designs are still under clinical trials. One of such techniques is the injection of CAR-T cells to fight against the COVID-19 infection. In this manuscript, the hypothesis is based on the CAR-T cells, that are suitably engineered towards SARS-2 viral antigen, by the N protein. The N protein binds to the SARS-2 viral RNA and is found in abundance in this virus, thus for the engineered cell research, this protein sequence is chosen as a potential target. The use of the sub-population of T-reg cells is also outlined. Mathematical modeling of such complex line of action can help to understand the dynamics. The modeling approach is inspired from the probabilistic rules, including the branching process, the Moran process and kinetic models. The Moran processes are well recognized in the fields of artificial intelligence and data science. The model depicts the infectious axis "virus-CAR-T cells-memory cells". The theoretical analysis provides a positive therapeutic action; the delay in viral production may have a significant impact on the early stages of infection. Although it is necessary to carefully evaluate the possible side effects of therapy. This work introduces the possibility of hypothesizing an antiviral use by CAR-T cells.

COVID-19 Variants and Transfer Learning for the Emerging Stringency Indices.

The pandemics in the history of world health organization have always left memorable hallmarks, on the health care systems and on the economy of highly effected areas. The ongoing pandemic is one of the most harmful pandemics and is threatening due to its transformation to more contiguous variants. Here in this manuscript, we will first outline the variants and then their impact on the associated health issues. The deep learning algorithms are useful in developing models, from a higher dimensional problem/ dataset, but these algorithms fail to provide insight during the training process and do not generalize the conditions. Transfer learning, a new subfield of machine learning has acquired fame due to its ability to exploit the information/learning gained from a previous process to improve generalization for the next. In short, transfer learning is the optimization of the stored knowledge. With the aid of transfer learning, we will show that the stringency index and cardiovascular death rates were the most important and appropriate predictors to develop the model for the forecasting of the COVID-19 death rates.

Modeling the crossover behavior of the bacterial infection with the COVID-19 epidemics.

To explore the crossover linkage of the bacterial infections resulting from the viral infection, within the host body, a computational framework is developed. It analyzes the additional pathogenic effect of Streptococcus pneumonia, one of the bacteria that can trigger the super-infection mechanism in the COVID-19 syndrome and the physiological effects of innate immunity for the control or eradication of this bacterial infection. The computational framework, in a novel manner, takes into account the action of pro-inflammatory and anti-inflammatory cytokines in response to the function of macrophages. A hypothetical model is created and is transformed to a system of non-dimensional mathematical equations. The dynamics of three main parameters (macrophages sensitivity κ , sensitivity to cytokines η and bacterial sensitivity ϵ ), analyzes a "threshold value" termed as the basic reproduction number R 0 which is based on a sub-model of the inflammatory state. Piece-wise differentiation approach is used and dynamical analysis for the inflammatory response of macrophages is studied in detail. The results shows that the inflamatory response, with high probability in bacterial super-infection, is concomitant with the COVID-19 infection. The mechanism of action of the anti-inflammatory cytokines is discussed during this research and it is observed that these cytokines do not prevent inflammation chronic, but only reduce its level while increasing the activation threshold of macrophages. The results of the model quantifies the probable deficit of the biological mechanisms linked with the anti-inflammatory cytokines. The numerical results shows that for such mechanisms, a minimal action of the pathogens is strongly amplified, resulting in the "chronicity" of the inflammatory process.

Forecasting of the efficiency of monoclonal therapy in the treatment of CoViD-19 induced by the Omicron variant of SARS-CoV2.

On November 26, 2021, the World Health Organization (WHO) announced a new variant of concern of SARS-CoV2 called Omicron. This variant has biological-functional characteristics such as to make it much faster in the infectious process so as to show an even more intense spread. Although many data are currently incomplete, it is possible to identify, based on the viral biochemical characteristics, a possible therapy consisting of a monoclonal antibody called Sotrovimab. The model proposed here is based on the mathematical analysis of the dynamics of action of this monoclonal antibody and two cell populations: the immune memory cells and the infected cells. Indeed, a delay exists during the physiological immune response and the response induced by administration of Sotrovimab. This manuscript presents that delay in a novel manner. The model is developed with the aid of information based on the chemical kinetics. The machine learning tools have been used to satisfy the criteria designed by the dynamical analysis. Regression learner tools of Python are used as the reverse engineering tools for the understanding of the balance in the mathematical model, maintained by the parameters and their corresponding intervals and thresholds set by the dynamical analysis.

Piecewise differentiation of the fractional order CAR-T cells-SARS-2 virus model.

The pandemic caused by the SARS-CoV2 virus has prompted research into new therapeutic solutions that can be used to treat the CoVid-19 syndrome. As part of this research, immunotherapy, first developed against cancer, is offering new therapeutic horizons also against viral infections. CAR technology, with the production of CAR-T cells (adoptive immunotherapy), has shown applicability in the field of HIV viral infections through second generation CAR-T cells implemented with the "CD4CAR" system with a viral fusion inhibitor. In addition, to avoid the immunoescape of the virus, bi- or trispecific CAR receptors have been developed. Our research group hypothesizes the use of this immunotherapy system against SARS-CoV2, admitting the appropriate adjustments concerning the target-epitope and a possible remodeling of the nuclease related to the action of this virus. For a more in-depth analysis of this hypothesis, a mathematical model has been developed which, starting from the fractional derivative Caputo, creates a system of equations that describes the interactions between CAR-T cells, memory cells, and cells infected with SARS-CoV2. Through an analysis of the existence and non-negativity of the solutions, the hypothesis is stabilized; then is further demonstrated through the use of the piece-wise derivative and the consequent application of the formula of Newton polynomial interpolation.

PARADIGMS OF COVID-19 AND THE CYTOKINE THERAPY APPROACHES: APPLICATIONS, BASIS, AND COMMUNICATIONS

One of the complications caused by the viral agent SARS-CoV2 is atypical pneumonia that occurs classically in viral pathologies. These infection complications produce a sort of “cytokine release syndrome” that sees interleukin 6, a glycosylated protein of approximately 212 amino acids, among the leading players in the inflammatory process. IL-6 typically produces a transient inflammatory state that promotes the host’s immune defence through its pleiotropic function. There is the stimulation of a response in the acute infectious phase, hematopoiesis and the regular advent of immune reactions. The action of the anti-inflammatory cytokines, which tends to regulate the inflammatory one’s activity, is directed to the same cells that produce IL-6, which, through an inhibition mechanism, slow down or production ceases altogether. Evidently, in the case of the IL-6 storm, the action of these anti-inflammatory cytokines is insufficient, and the blockade of IL-6R receptors and through the use of monoclonal antibody-like tocilizumab has proved to be optimal to manage complications and avoid potentially fatal situations. Therefore, the purpose of this paper is to create a mathematical model that describes the action of the IL-6 cytokine in SARS-CoV2 virus infection to understand better the extent of the disease itself and the associated severe side effects. We represent the concentration of tocilizumab, soluble IL-6R, absolute neutrophils and circulating platelets using computational modeling. Tocilizumab is administered by intravenous infusions with a minimum dose of 80mg and a maximum dose of 400mg. Following tocilizumab administration, simulation results indicate that the population of absolute neutrophils and circulating platelets is decreasing. After the removal of tocilizumab concentration, both absolute neutrophils and circulating platelets return at their baselines.

Forecasting the action of CAR-T cells against SARS-corona virus-II infection with branching process

The CAR-T cells are the genetically engineered T cells, designed to work specifically for the virus antigens (or other antigens, such as tumour specific antigens). The CAR-T cells work as the living drug and thus provides an adoptive immunotherapy strategy. The novel corona virus treatment and control designs are still under clinical trials. One of such techniques is the injection of CAR-T cells to fight against the COVID-19 infection. In this manuscript, the hypothesis is based on the CAR-T cells, that are suitably engineered towards SARS-2 viral antigen, by the N protein. The N protein binds to the SARS-2 viral RNA and is found in abundance in this virus, thus for the engineered cell research, this protein sequence is chosen as a potential target. The use of the sub-population of T-reg cells is also outlined. Mathematical modeling of such complex line of action can help to understand the dynamics. The modeling approach is inspired from the probabilistic rules, including the branching process, the Moran process and kinetic models. The Moran processes are well recognized in the fields of artificial intelligence and data science. The model depicts the infectious axis “virus—CAR-T cells—memory cells”. The theoretical analysis provides a positive therapeutic action;the delay in viral production may have a significant impact on the early stages of infection. Although it is necessary to carefully evaluate the possible side effects of therapy. This work introduces the possibility of hypothesizing an antiviral use by CAR-T cells.

Forecasting the impact of environmental stresses on the frequent waves of COVID19.

A novel approach to link the environmental stresses with the COVID-19 cases is adopted during this research. The time-dependent data are extracted from the online repositories that are freely available for knowledge and research. Since the time series data analysis is desired for the COVID-19 time-dependent frequent waves, here in this manuscript, we have developed a time series model with the aid of "nonlinear autoregressive network with exogenous inputs (NARX)" approach. The distribution of infectious agent-containing droplets from an infected person to an uninfected person is a common form of respiratory disease transmission. SARS-CoV-2 has mainly spread via short-range respiratory droplet transmission. Airborne transmission of SARS-CoV-2 seems to have occurred over long distances or times in unusual conditions; SARS-CoV-2 RNA was found in PM10 collected in Italy. This research shows that SARS-CoV-2 particles adsorbed to outdoor PM remained viable for a long time, given the epidemiology of COVID-19, outdoor air pollution is unlikely to be a significant route of transmission. In this research, ANN time series is used to analyze the data resulting from the COVID-19 first and second waves and the forecasted results show that air pollution affects people in different areas of Italy and make more people sick with covid-19. The model is developed based on the disease transmission data of Italy.

Furin and the adaptive mutation of SARS-COV2: a computational framework.

SARS-2 virus has reached its most harmful mutated form and has damaged the world's economy, integrity, health system and peace to a limit. An open problem is to address the release of antibodies after the infection and after getting the individuals vaccinated against the virus. The viral fusion process is linked with the furin enzyme and the adaptation is linked with the mutation, called D614G mutation. The cell-protein studies are extremely challenging. We have developed a mathematical model to address the process at the cell-protein level and the delay is linked with this biological process. Genetic algorithm is used to approximate the parametric values. The mathematical model proposed during this research consists of virus concentration, the infected cells count at different stages and the effect of interferon. To improve the understanding of this model of SARS-CoV2 infection process, the action of interferon (IFN) is quantified using a variable for the non-linear mathematical model, that is based on a degradation parameter γ . This parameter is responsible for the delay in the dynamics of this viral action. We emphasize that this delay responds to the evasion by SARS-CoV2 via antagonizing IFN production, inhibiting IFN signaling and improving viral IFN resistance. We have provided videos to explain the modeling scheme.

Self organizing maps for the parametric analysis of COVID-19 SEIRS delayed model.

Since 2019, entire world is facing the accelerating threat of Corona Virus, with its third wave on its way, although accompanied with several vaccination strategies made by world health organization. The control on the transmission of the virus is highly desired, even though several key measures have already been made, including masks, sanitizing and disinfecting measures. The ongoing research, though devoted to this pandemic, has certain flaws, due to which no permanent solution has been discovered. Currently different data based studies have emerged but unfortunately, the pandemic fate is still unrevealed. During this research, we have focused on a compartmental model, where delay is taken into account from one compartment to another. The model depicts the dynamics of the disease relative to time and constant delays in time. A deep learning technique called "Self Organizing Map" is used to extract the parametric values from the data repository of COVID-19. The input we used for SOM are the attributes on which, the variables are dependent. Different grouping/clustering of patients were achieved with 2- dimensional visualization of the input data ( h t t p s : / / c r e a t i v e c o m m o n s . o r g / l i c e n s e s / b y / 2.0 / ). Extensive stability analysis and numerical results are presented in this manuscript which can help in designing control measures.

Delayed Modeling Approach to Forecast the Periodic Behavior of SARS-2.

The ongoing threat of Coronavirus is alarming. The key players of this virus are modeled mathematically during this research. The transmission rates are hypothesized, with the aid of epidemiological concepts and recent findings. The model reported is extended, by taking into account the delayed dynamics. Time delay reflects the fact that the dynamic behavior of transmission of the disease, at time t depends not only on the state at time t but also on the state in some period τ before time t. The research presented in this manuscript will not only help in understanding the current threat of pandemic (SARS-2), but will also contribute in making precautionary measures and developing control strategies.

COMPUTATIONAL FRAMEWORK TO EXPLORE IMPACT OF ENVIRONMENTAL STRESS ON EPIDEMICS: APPLICATIONS, BASIS, AND COMMUNICATIONS

In the field of epidemiology, not only the disease and the carriers, but also the surrounding environment and the associated stresses play a vital role. Environmental stresses in a novel habitat may facilitate adaptive shifts. Organisms living under environmental stresses often experience higher mutation rates and display greater phenotypic and genetic variation. There is controversial evidence available in the literature about the impact of environmental stresses on the organisms and the resulting variation in mutation rates and the immune responses. In nature, “selection” and the high energetic costs of stress usually reduce this variation. The prior knowledge of the interaction between the stress and disease epidemics may help to control the disease spread at an early stage. A mathematical model of epidemiology, specifically focusing on the vector borne diseases, with environmental stress is reported in this paper. The model is validated with the aid of stability analysis. During this research, a set of parametric values is obtained using reverse engineering. For this purpose, the parametric evaluation is reported with the help of Monte Carlo Markov Chain (MCMC) reverse engineering. Among other factors, the environmental stresses are also responsible for different dynamics of the same disease, in different continents of the world. The proposed research methodology will help in forecasting the epidemiological problems such as the current threat of coronavirus.

Modeling and simulations of CoViD-19 molecular mechanism induced by cytokines storm during SARS-CoV2 infection.

It is highly desired to explore the interventions of COVID-19 for early treatment strategies. Such interventions are still under consideration. A model is benchmarked research and comprises target cells, virus infected cells, immune cells, pro-inflammatory cytokines, and, anti-inflammatory cytokine. The interaction of the drug with the inflammatory sub-system is analyzed with the aid of kinetic modeling. The impact of drug therapy on the immune cells is modelled and the computational framework is verified with the aid of numerical simulations. The work includes a significant hypothesis that quantifies the complex dynamics of the infection, by relating it to the effect of the inflammatory syndrome generated by IL-6. In this paper we use the cancer immunoediting process: a dynamic process initiated by cancer cells in response to immune surveillance of the immune system that it can be conceptualized by an alternating movement that balances immune protection with immune evasion. The mechanisms of resistance to immunotherapy seem to broadly overlap with those used by cancers as they undergo immunoediting to evade detection by the immune system. In this process the immune system can both constrain and promote tumour development, which proceeds through three phases termed: (i) Elimination, (ii) Equilibrium, and, (iii) Escape [1]. We can also apply these concepts to viral infection, which, although it is not exactly "immunoediting", has many points in common and helps to understand how it expands into an "untreated" host and can help in understanding the SARS-CoV2 virus infection and treatment model.

Forecasting the timeframe of 2019-nCoV and human cells interaction with reverse engineering.

In December 2019, an atypical pneumonia invaded the city of Wuhan, China, and the causative agent of this disease turned out to be a new coronavirus. In January 2020, the World Health Organization named the new coronavirus 2019-nCoV and subsequently it is referred to as SARS-CoV2 and the related disease as CoViD-19 (Lai et al., 2020). Very quickly, the epidemic led to a pandemic and it is now a worldwide emergency requiring the creation of new antiviral therapies and a related vaccine. The purpose of this article is to review and investigate further the molecular mechanism by which the SARS-CoV2 virus infection proceeds via the formation of a hetero-trimer between its protein S, the ACE2 receptor and the B0AT1 protein, which is the "entry receptor" for the infection process involving membrane fusion (Li et al., 2003). A reverse engineering process uses the formalism of the Hill function to represent the functions related to the dynamics of the biochemical interactions of the viral infection process. Then, using a logical evaluation of viral density that measures the rate at which the cells are hijacked by the virus (and they provide a place for the virus to replicate) and considering the "time delay" given by the interaction between cell and virus, the expected duration of the incubation period is predicted. The conclusion is that the density of the virus varies from the "exposure time" to the "interaction time" (virus-cells). This model can be used both to evaluate the infectious condition and to analyze the incubation period. BACKGROUND: The ongoing threat of the new coronavirus SARS-CoV2 pandemic is alarming and strategies for combating infection are highly desired. This RNA virus belongs to the ß-coronavirus genus and is similar in some features to SARS-CoV. Currently, no vaccine or approved medical treatment is available. The complex dynamics of the rapid spread of this virus can be demonstrated with the aid of a computational framework. METHODS: A mathematical model based on the principles of cell-virus interaction is developed in this manuscript. The amino acid sequence of S proein and its interaction with the ACE-2 protein is mimicked with the aid of Hill function. The mathematical model with delay is solved with the aid of numerical solvers and the parametric values are obtained with the help of MCMC algorithm. RESULTS: A delay differential equation model is developed to demonstrate the dynamics of target cells, infected cells and the SARS-CoV2. The important parameters and coefficients are demonstrated with the aid of numerical computations. The resulting thresholds and forecasting may prove to be useful tools for future experimental studies and control strategies. CONCLUSIONS: From the analysis, I is concluded that control strategy via delay is a promising technique and the role of Hill function formalism in control strategies can be better interpreted in an inexpensive manner with the aid of a theoretical framework.